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Targeting the genome stability hub Ctf4 by stapled-peptide design

DOI: 10.1002/anie.201705611 DOI Help

Authors: Yuteng Wu (University of Cambridge) , Fabrizio Villa (University of Dundee) , Joseph Maman (University of Cambridge) , Lina Dobnikar (University of Cambridge) , Yu H. Lau (University of Cambridge) , Aline C. Simon (University of Cambridge) , Karim Labib (University of Dundee) , David R. Spring (University of Cambridge) , Luca Pellegrini (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Angewandte Chemie International Edition

State: Published (Approved)
Published: August 2017

Abstract: Exploitation of synthetic lethality by small-molecule targeting of pathways that maintain genomic stability is an attractive chemotherapeutic approach. The Ctf4/AND-1 protein hub that links DNA replication, repair and chromosome segregation, represents a novel target for the synthetic lethality approach. Here we report the design, optimization, and validation of double-click stapled peptides encoding the Ctf4-interacting peptide (CIP) of the replicative helicase subunit Sld5. Screening stapling positions in the Sld5 CIP, we identified an unorthodox i,i+6 stapled peptide with improved, sub-micromolar binding to Ctf4. The mode of interaction with Ctf4 was confirmed by a crystal structure of the stapled Sld5 peptide bound to Ctf4. The stapled Sld5 peptide was able to displace the Ctf4-partner DNA polymerase alpha from the replisome in yeast extracts. Our study provides proof-of-principle evidence for the development of small-molecule inhibitors of the human-CTF4 orthologue AND-1.

Journal Keywords: Chemical biology; stapled peptides; protein-protein interactions; Ctf4 protein; chromosome stability

Subject Areas: Chemistry, Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography